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First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

ABSTRACT: Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). ⁶³Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of ⁶³Zn-zinc citrate (?330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral ⁶³Zn clearances were compared with ¹¹C-Pittsburgh Compound B (¹¹C-PiB) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) imaging data. ⁶³Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in ⁶³Zn clearance kinetics in relationship with regions of high amyloid-? plaque burden (¹¹C-PiB) and ¹⁸F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe ⁶³Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-? pathology, warranting further imaging studies of zinc homeostasis in patients with AD.

SUBMITTER: DeGrado TR

PROVIDER: S-EPMC5469518 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

DeGrado Timothy R TR Kemp Bradley J BJ Pandey Mukesh K MK Jiang Huailei H Gunderson Tina M TM Linscheid Logan R LR Woodwick Allison R AR McConnell Daniel M DM Fletcher Joel G JG Johnson Geoffrey B GB Johnson Geoffrey B GB Petersen Ronald C RC Knopman David S DS Lowe Val J VJ

Molecular imaging 20161209

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). <sup>63</sup>Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of <sup>63</sup>Zn-zinc citrate (∼330 MBq). Subsequently, body PET ...[more]

PMID: 27941122

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Project description:UnlabelledAlzheimer disease (AD) is a fatal neurodegenerative disorder characterized by progressive neuronal loss and cognitive decline. The lack of reliable and objective diagnostic markers for AD hampers early disease detection and treatment. Growing evidence supports the existence of a dysregulation in brain copper trafficking in AD. The aim of this study was to investigate brain copper trafficking in a transgenic mouse model of AD by PET imaging with (64)Cu, to determine its potential as a diagnostic biomarker of the disorder.MethodsBrain copper trafficking was evaluated in 6- to 8-mo-old TASTPM transgenic mice and age-matched wild-type controls using the (64)Cu bis(thiosemicarbazone) complex (64)Cu-GTSM (glyoxalbis(N(4)-methyl-3-thiosemicarbazonato) copper(II)), which crosses the blood-brain barrier and releases (64)Cu bioreductively into cells. Animals were intravenously injected with (64)Cu-GTSM and imaged at 0-30 min and 24-25 h after injection. The images were analyzed by atlas-based quantification and texture analysis. Regional distribution of (64)Cu in the brain 24 h after injection was also evaluated via ex vivo autoradiography and compared with amyloid-β plaque deposition in TASTPM mice.ResultsCompared with controls, in TASTPM mice PET image analysis demonstrated significantly increased (by a factor of ~1.3) brain concentration of (64)Cu at 30 min (P < 0.01) and 24 h (P < 0.05) after injection of the tracer and faster (by a factor of ~5) (64)Cu clearance from the brain (P < 0.01). Atlas-based quantification and texture analysis revealed significant differences in regional brain uptake of (64)Cu and PET image heterogeneity between the 2 groups of mice. Ex vivo autoradiography showed that regional brain distribution of (64)Cu at 24 h after injection did not correlate with amyloid-β plaque distribution in TASTPM mice.ConclusionThe trafficking of (64)Cu in the brain after administration of (64)Cu-GTSM is significantly altered by AD-like pathology in the TASTPM mouse model, suggesting that (64)Cu-GTSM PET imaging warrants clinical evaluation as a diagnostic tool for AD and possibly other neurodegenerative disorders.

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First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

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First PET Imaging Studies With 63Zn-Zinc Citrate in Healthy Human Participants and Patients With Alzheimer Disease.

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